The only currently available treatment for end stage liver disease is liver transplantation. Since the number of patients on the liver transplant list far exceeds the number of donor organs available, alternative treatment methods, such as hepatic cell transplantation, are under intensive investigation. However, studies to date with adult hepatocytes have met with only very limited success, except for those performed in animal model systems under highly pathologic circumstances. Several years ago, our laboratory discovered that fetal liver stem/progenitor cells (FLSPC) can replace 20-25% of hepatic mass in the normal adult rat liver by entering into cell competition with host hepatocytes. Recently, we observed that the level of tissue replacement by FLSPC increases dramatically (5-fold) as rats age. In addition, we have discovered that the level of activin A, a mediator of cell cycle arrest, as well as apoptosis, is increased in the aging rat liver. We hypothesize that increased activin A expression in the aging liver creates a host tissue microenvironment favoring replacement of hepatocytes by transplanted FLSPC. We hypothesize further that activin A mediates increased repopulation in the aging liver through increased cell competition between transplanted FLSPC and host hepatocytes. The goal of this project is to determine the specific mechanism(s) by which activin A mediates liver repopulation by transplanted FLSPC. Experiments will be performed 1) to identify specific apoptosis, anti-apoptosis, proliferation, cell cycle and senescence related genes whose expression is increased or decreased during liver repopulation by transplanted FLSPC in older vs younger cell transplant recipients, 2) to study the mechanism in vitro for activin A induced growth arrest and apoptosis in isolated hepatic cells and 3) to determine in an experimental model of liver disease (i.e. hepatic fibrosis) whether liver repopulation by FLSPC is augmented by endogenous secretion of activin A. Since both the number and age of patients with end-stage liver diseases will continue to increase over the next twenty years, the potential use of cell transplantation to treat these patients before the end-stage would be of substantial clinical benefit, especially in the elderly. Therefore, identifying the specific cell type(s) for effective cell transplantation to replace hepatic parenchyma and restore liver function in elderly patients with chronic liver diseases would represent a particularly valuable therapy. Results from the proposed studies will also provide critical understanding of the basic requirements and mechanisms that will serve as a guide for effective liver repopulation in patients of all ages. PUBLIC HEALTH RELEVANCE: We have found that repopulation of adult rat liver with transplanted fetal liver cells increases with the age of the recipient and can be achieved in rats with advanced hepatic fibrosis. Since whole liver transplants are generally not performed in patients beyond age 65, if our findings are applicable to humans, this suggests that liver cell transplantation would represent a major new therapeutic approach for treatment of chronic liver diseases, especially in the elderly.